Allergic asthma is characterized by variable reversible airway obstruction, and airway hyperresponsiveness associated with airway inflammation. The inflammation is itself characterized by the presence of activated mast cells and eosinophils, which through the generation of proinflammatory mediators and cytokines play a fundamental role in the pathogenesis of the disease. The eosinophil is thought to be a major effector cell in the development of airway hyperresponsiveness, through the release of cytotoxic granule proteins. However, the initial induction of IgE-mediated mast cell activation/degranulation constitutes the primary mechanism that drives the allergic airway response and changes in airway physiology. Activation of mast cells by cross linking of IgE leads to the release of histamine and generation of leukotrienes that appear to contribute to the early bronchoconstriction occurring within minutes of allergen exposure. Moreover, the production of cytokines (TNF, IL-4, IL-5), angiogenic and fibrotic factors, and the release of chemokines (RANTES, eotaxin, MCP-1, TARC) which favor the infiltration of the airway tissues with eosinophils and lymphocytes, drive/enhance the maintenance and progression of the disease. The relationship between mast cell activation and eosinophil recruitment has substantial consequences on the pathogenesis of asthma.
Stem Cell Factor (SCF; also known as Mast Cell Growth Factor, Steel Factor or c-kit ligand) is an important hematopoietic factor that drives the differentiation of mast cells in the bone marrow. SCF as a result of alternate splicing exists as a membrane bound and soluble form and is produced by bone marrow stromal cells. SCF is also produced by several cell types found in peripheral tissues including fibroblasts, endothelial cells, epithelial cells, mast cells and eosinophils, and is thought to be the primary cytokine regulating the survival, activation, and degranulation of mature mast cells in the lung microenvironment. In addition to IgE mediated activation of mast cells, SCF can directly induce mast cell activation and degranulation resulting in the release of inflammatory mediators, cytokines and chemokines as discussed above. Moreover, SCF strongly augments the IgE-mediated activation of mast cells. The prolonged activation of local airway mast cell populations by SCF after initial IgE-mediated activation may play a significant role in persistent activation leading to prolonged impairment of lung function. SCF also induces mast cell adhesion to extra cellular matrix proteins as well as their chemotaxis. SCF has also demonstrated a direct role on eosinophil adhesion by altering avidity of VLA-4 on the surface of eosinophils which has significant consequences for eosinophil migration to the lung.
In vivo administration of SCF to the airways has been shown to be a potent inducer of airway hyperreactivity and inflammation in mice (Lukacs et al., J. Immunol., 156: 3945 (1996); Campbell et al., Am. J. Pathol., 154:1259 (1999). Recently, published studies have demonstrated therapeutic benefit of inhibitors of SCF, either antibodies or antisense RNA, in treating antigen-induced asthma in rodent models (Campbell et al., Am. J. Pathol., 154:1259 (1999).; Finotto et al., J. Allergy Clin. Immunol., 107:279 (2001)).
It is an object of the invention to provide reagents and methods of inhibiting stem cell factor activity.